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Lactate Limits T Cell Proliferation via the NAD(H) Redox State.

Cell reports (2020-12-17)
William J Quinn, Jing Jiao, Tara TeSlaa, Jason Stadanlick, Zhonglin Wang, Liqing Wang, Tatiana Akimova, Alessia Angelin, Patrick M Schäfer, Michelle D Cully, Caroline Perry, Piotr K Kopinski, Lili Guo, Ian A Blair, Louis R Ghanem, Michael S Leibowitz, Wayne W Hancock, Edmund K Moon, Matthew H Levine, Evgeniy B Eruslanov, Douglas C Wallace, Joseph A Baur, Ulf H Beier
ABSTRACT

Immune cell function is influenced by metabolic conditions. Low-glucose, high-lactate environments, such as the placenta, gastrointestinal tract, and the tumor microenvironment, are immunosuppressive, especially for glycolysis-dependent effector T cells. We report that nicotinamide adenine dinucleotide (NAD+), which is reduced to NADH by lactate dehydrogenase in lactate-rich conditions, is a key point of metabolic control in T cells. Reduced NADH is not available for NAD+-dependent enzymatic reactions involving glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and 3-phosphoglycerate dehydrogenase (PGDH). We show that increased lactate leads to a block at GAPDH and PGDH, leading to the depletion of post-GAPDH glycolytic intermediates, as well as the 3-phosphoglycerate derivative serine that is known to be important for T cell proliferation. Supplementing serine rescues the ability of T cells to proliferate in the presence of lactate-induced reductive stress. Directly targeting the redox state may be a useful approach for developing novel immunotherapies in cancer and therapeutic immunosuppression.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Resazurin sodium salt, powder, BioReagent
Sigma-Aldrich
Riboflavin 5′-monophosphate sodium salt hydrate, 73-79% (fluorimetric)
Sigma-Aldrich
Sodium L-lactate, ~98%
Sigma-Aldrich
D-Glucose-13C6, ≥99 atom % 13C, ≥99% (CP)
Sigma-Aldrich
Alcohol Dehydrogenase from Saccharomyces cerevisiae, powder, ≥300 units/mg protein, mol wt ~141,000 (four subunits)
Sigma-Aldrich
Diaphorase from Clostridium kluyveri, lyophilized powder, 3.0-20.0 units/mg protein (biuret)
Sigma-Aldrich
L-Serine, ReagentPlus®, ≥99% (HPLC)
Sigma-Aldrich
Nicotinamide, ≥98.5% (HPLC)